Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240

Fenton, TR, Nathanson, D, de Albuquerque, C Ponte, Kuga, D, Iwanami, A, Dang, J, Yang, H, Tanaka, K, Oba-Shinjo, SM, Uno, M, and others. (2012) Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240. Proceedings of the National Academy of Sciences, 109 (35). 14164 - 14169. ISSN 0027-8424. (doi:10.1073/pnas.1211962109) (KAR id:61514)

PDF Publisher pdf Language: English
Download this file (PDF/976kB)	Preview
Request a format suitable for use with assistive technology e.g. a screenreader
Official URL: http://dx.doi.org/10.1073/pnas.1211962109

Abstract

Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3'-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings show that, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.

Item Type:	Article
DOI/Identification number:	10.1073/pnas.1211962109
Additional information:	PMCID: PMC3435194
Uncontrolled keywords:	Animals, Astrocytes, Brain Neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Disease Models, Animal, Drug Resistance, Neoplasm, Glioblastoma, Humans, Mice, Mice, Mutant Strains, Mice, Nude, PTEN Phosphohydrolase, Phosphorylation, Protein Kinase Inhibitors, Quinazolines, Receptor, Epidermal Growth Factor, Signal Transduction, Transplantation, Heterologous, Tumor Cells, Cultured, Tyrosine
Divisions:	Divisions > Division of Natural Sciences > Biosciences
Depositing User:	Tim Fenton
Date Deposited:	23 May 2017 16:46 UTC
Last Modified:	16 Nov 2021 10:24 UTC
Resource URI:	https://kar.kent.ac.uk/id/eprint/61514 (The current URI for this page, for reference purposes)

University of Kent Author Information

Fenton, TR.

Creator's ORCID:	https://orcid.org/0000-0002-4737-8233
CReDIT Contributor Roles:

Depositors only (login required):

Altmetric

Download Statistics

Total unique views for this document in KAR since July 2020. For more details click on the image.